The role of Peripheral CGRP in a preclinical mouse model of migraine

项目总结/摘要 偏头痛是一种复杂的和衰弱的神经系统疾病，涉及神经肽降钙素基因- 相关肽（CGRP）。本项目的总体目标是确定外围设备 CGRP导致光恐惧症，这是一种对非有害光水平的痛苦反应，约90%的人经历过这种反应。 偏头痛患者外周注射CGRP引起光厌恶，类似于 恐惧症。野生型小鼠的这种反应需要明亮的光线，而在转基因小鼠中， 增加CGRP受体，即使在昏暗的光线下也可以看到增强的反应。有趣的是， 在具有升高的神经系统的转基因小鼠中没有观察到增强的光厌恶表型 受体的表达。这一证据表明，外周CGRP管理可能会导致光 厌恶和激活神经通路的间接机制。由于CGRP是最有效的 由于CGRP是体内的血管扩张剂，我们推测CGRP可通过血管机制引起光厌恶。 该假设基于以下发现：1）在人类受试者中静脉内施用CGRP可以 引起偏头痛，2）血管周围CGRP可使三叉神经敏感，这可能会改变 突触传递到中枢神经系统。因此，存在一种机制，通过该机制， 周围神经的刺激可以使三叉神经敏感，改变感觉知觉，导致恐惧症。单个 提出了将建立脉管系统在光厌恶行为中的贡献的目标。 将使用补充的药理学和遗传学策略。药理学方法将是 共同给予血管收缩剂以最小化CGRP诱导的血管舒张。遗传学的方法将是 在内皮细胞和平滑肌细胞上产生条件性过表达CGRP受体的转基因小鼠 血管系统的肌肉细胞这一目标将提供深入了解的机制， CGRP可以在偏头痛的临床前小鼠模型中触发偏头痛样症状。

Project Summary/Abstract Migraine is a complex and debilitating neurological disorder involving the neuropeptide calcitonin gene- related peptide (CGRP). The overall objective of this project is to identify mechanisms by which peripheral CGRP causes photophobia, a painful response to non-noxious levels of light experienced by ~90% of migraine patients. Peripheral injection of CGRP causes light aversion, a response analogous to photophobia. This response in wild-type requires bright light, while in transgenic mice with globally increased CGRP receptors there is an enhanced response seen even in dim light. Interestingly, this enhanced light aversive phenotype is not seen in transgenic mice that have elevated nervous system expression of the receptor. This evidence suggests that peripheral CGRP administration may cause light aversion and activate neural pathways in an indirect mechanism. Since CGRP is one of the most potent vasodilators in the body, we hypothesize that CGRP can cause light aversion by a vascular mechanism. This hypothesis is based on findings that 1) intravenous administration of CGRP in human subjects can cause migraine pain, and 2) perivascular CGRP can sensitize the trigeminal nerve, which could alter synaptic transmission to the central nervous system. Thus, there is a mechanism by which CGRP in the periphery can sensitize the trigeminal nerve and alter sensory perception, leading to photophobia. A single aim is proposed that will establish the contribution of the vasculature in light aversive behavior. Complementary pharmacological and genetic strategies will be used. The pharmacological approach will be to co-administer a vasoconstrictor to minimize CGRP-induced vasodilation. The genetic approach will be to generate transgenic mice with conditional overexpression of CGRP receptors on endothelial and smooth muscle cells of the vasculature. This aim will provide insight into the mechanisms by which peripheral CGRP can trigger a migraine-like symptom in a preclinical mouse model of migraine.